Ceftolozane is a cephalosporin antibacterial agent, also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl ethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate. Ceftolozane sulfate is a pharmaceutically acceptable ceftolozane salt of compound (VI), in FIG. 1A, that can be formulated for intravenous administration or infusion.
Ceftolozane can be obtained using methods described in U.S. Pat. No. 7,192,943 and Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205,” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), incorporated herein by reference in its entirety. Referring to FIGS. 1B and 1C, synthesis of ceftolozane is disclosed from the starting material thiadiazolyl-oximinoacetic acid (compound (I)) also referred to as TATD. Activation of carboxylic acid group of thiadiazolyl-oximinoacetic acid (compound (I)) is carried out by methanesulfonyl chloride and potassium carbonate in a conventional solvent such as N, N-dimethylacetamide to yield the activated thiadiazolyl-oximinoacetic acid methanesulfonate ester (Ib). The reaction of activated thiadiazolyl-oximinoacetic acid (compound (Ib)) and 7-aminocephem compound (II) is disclosed to yield compound (III), which can be further reacted with 4-[(N-Boc-aminoethyl)carbamoylamino]-1-methyl-5-tritylaminopyrazole (IV) to obtain ceftolozane intermediate compound (V). The ceftolozane intermediate (compound (V)) is globally deprotected using a mixture of trifluoroacetic acid (TFA) and anisole to yield ceftolozane trifluoroacetate compound (Vb), which is further crystallized from a mixture of sulfuric acid and wet isopropanol to afford ceftolozane sulfate (compound (VI)).
Given the multi-step process for making ceftolozane, there remains a need for approaches to performing individual steps in the synthesis of ceftolozane with desirably high yields (e.g., at least about 90%), as well as ceftolozane intermediates useful in the manufacture of ceftolozane. Most of the ceftolozane synthetic methods as referenced herein are based on optimizing the synthesis of the intermediates or changing the order of the reactants or intermediates added during the reaction. This can include, for example, activation of the thiadiazolyl-oximinoacetic acid (I) with phosphoryl chloride in a conventional solvent such as N, N-dimethylformamide to obtain an acid halide compound, which is further reacted with 7-aminocephem compound (II) followed by a series of subsequent reactions to obtain ceftolozane sulfate (compound (VI)) (see, e.g., U.S. Pat. No. 7,129,232). As disclosed in U.S. Pat. No. 7,192,943, activation of the thiadiazolyl-oximinoacetic acid (compound (I)) can also be carried out with methanesulfonyl chloride in a conventional solvent such as N, N-dimethylacetamide to obtain a acid halide compound, which is further reacted with 7-aminocephem compound (II) followed by series of reactions to obtain ceftolozane sulfate (compound (VI)).
There remains a need for improved methods for the synthesis of compounds (Ib) and compound (III) with desirably high yields for various reasons, including ceftolozane synthesis. In particular, there is need for methods providing a desirably high yield of the conversion of compound (I) into compound (Ib), and to control the yield of the intermediates such as compound (III), which can be used in the subsequent steps to manufacture ceftolozane sulfate (compound (VI)). Higher yield processes can reduce manufacturing costs associated with, for example, the starting material TATD compound (I), which can be commercially obtained as [(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino) acetic acid], (CAS 76028-96-1). Compound (I) can be an expensive starting material used during the manufacturing of ceftolozane sulfate, so it is desirable to identify synthetic processes that utilize lower equivalents of compound (I); however, greater guidance is needed to improve the yield of certain intermediates in the manufacture of ceftolozane. For example, one step of the process comprises synthesizing compound (III) by reacting compound (II) with compound (Ib), which is obtained via the activation of compound (I).